DESCRIPTION: Vpr and Vpx are two of the least well understood lentivirus regulatory genes. Previous studies from this investigator's laboratory have demonstrated that Vpr expression in cells dramatically inhibits the activity of the "molecular clock" that drives the cell cycle. Vpr prevents activation of the Cdc2/cyclin B at the G2/M border in the cell cycle, an event required to initiate the events of M phase. As a result, the HIV-1 infected cells are arrested in G2. By preventing Cdc2 activation, Vpr could block transduction of apoptotic signals to the nucleus. This would increase the life span of infected cells and provide a selective advantage to the virus. The goal of these studies then is to understand the biochemical basis of Vpr and Vpx induced Cdc2 inhibition and to understand the selective advantage that this provides to HIV in vivo. The following specific aims are proposed: Specific Aim 1: To understand the biochemical basis by which Vpr and Vpx inhibit Cdc2 activation. Specific Aim 2: To determine whether Vpr or Vpx blocks Fas, TNF-alpha or CTL-induced apoptosis. Specific Aim 3: To identify a cellular protein that interacts with Vpr.